The single strand viral RNA genome of dengue type 4 virus has been completely sequenced. The genome contains 10,644 nucleotides with a single long open reading frame that encodes a polyprotein of 3386 amino acids. The polyprotein is cleaved post-translationally into the full complement of viral proteins by a mechanism similar to that proposed for gene expression of other flaviviruses. Homology alignment of the dengue type 4 virus polyprotein with the polyproteins of two other flaviviruses, yellow fever and West Nile viruses, indicated that the 5' end of the dengue viral RNA encodes three structural proteins designated capsid (C), matrix (M) and envelope (E). The 3' terminal 7500 nucleotides encode seven nonstructural (NS) proteins designated NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. NS1 is the major NS glycoprotein produced during viral infection, while NS3 and NS5 contain polymerase-like amino acid sequences. Except for NS1, the function of dengue NS proteins is not known. Dengue NS proteins are more highly related to West Nile (WN) or Murray Valley encephalitis (MVE) virus NS proteins than to yellow fever (YF) virus NS proteins. In the region of the polyprotein containing the nonstructural proteins there is considerable conservation of hydrophobicity and a consensus sequence prevails at many proteolytic cleavage sites implying a close functional relationship for corresponding NS proteins. In view of the recent finding that the YF NS1 induces resistance in mice to challenge with YF virus, it is likely that the analogous dengue NS1 protein may prove useful in immunoprophylaxis against dengue infection.